DCEG has a long and distinguished history of investigating the relationship between treatments administered to patients to control an initial cancer, and the risk of subsequently developing a second cancer. This represents a unique observational situation in which one can study the consequences of human exposure to well defined chemical carcinogens and to ionizing radiation. The opportunity now exists to move these studies into the genetic arena, by investigating the relationship between common polymorphisms in genes affecting the bioavailability of chemical carcinogens and various outcomes of clinical interest. Such studies could identify population sub-groups which are at particular risk of second cancers, thrombotic events, acute myelosuppression, response to treatment or even survival. The potential also exists to identify genetic variants which may reduce the risk of adverse outcomes. Information of this kind could have a significant impact on clinical decision-making. (a) CGB's first foray into this arena is now well underway: we are planning a study of genetic polymorphisms in the genes related to tamoxifen and estrogen bioavailability and the risk of developing endometrial cancer and breast cancer as a result of exposure to tamoxifen. Clinical trials have demonstrated that women exposed to tamoxifen are at increased risk of developing endometrial cancer and at decreased risk of developing breast cancer. In general terms, these differences have been attributed to tissue specific variations in whether tamoxifen acts as an estrogen agonist or an estrogen antagonist. We hypothesize that genetic variations in the genes which affect tamoxifen and/or estrogen metabolism may identify sub-groups of women who are more or less likely to benefit from the administration of tamoxifen. It is hoped that this study will be conducted using banked DNA specimens from women who participated in NSABP's Tamoxifen Breast Cancer Prevention Trial. This proposal is now under review at NSABP. Laboratory work required to develop the assays for the polymorphisms selected for study is nearly complete. (b) Another variation on the theme of common variants within less penetrant genes as modifiers of cancer risk is our ongoing study of genetic polymorphisms in genes which are part of the IGF1 signaling pathway. Elevated levels of IGF1, a cytokine with both mitogenic and anti-apoptotic effects, have been associated with increased risks of a variety of different cancers, including premenopausal breast, colon, prostate and lung cancer. In collaboration with the Laboratory of Population Genetics and the Office of the Director, Epidemiology & Biostatistics Program, genetic variations in these genes are being systematically identified and then studied as determinants of neoplasm risk among participants of the Prostate, Lung, Colon and Ovarian Cancer screening trial. (c) It is anticipated that opportunities for other analyses of the relationship between common genetic variants and the risk of various cancer treatment-related outcomes will be sought and identified. Particularly promising is the opportunity of working with various national clinical trials cooperative groups, both to explore the possibilities of using archived tumor samples as a source of DNA for gene study, as well as to consider the prospective collection of germline DNA from participants in selected clinical trials. Among the ideas under consideration are an evaluation of genetic influences upon the risk of developing contralateral breast cancer and acute leukemia among women with breast cancer participating in clinical trials, and the option of extending our studies of tamoxifen and endometrial cancer into other historical clinical trials cohorts. An experienced DCEG Principal Investigator, Dr. Charles Rabkin, has joined CGB for a sabbatical year to assist in the development of this program. Dr. Rabkin will build on his expertise related to genetic polymorphisms in various cytokine genes as risk factors for gastric cancer. (d) CGB staff are providing cancer genetics consultation to the Food and Drug Administration in support of its investigation of a cluster of malignant lymphomas which has been identified among patients exposed to a novel class of therapeutic agents, the tumor necrosis factor inhibitors. These medications have been approved recently for the treatment of refractory rheumatoid arthritis and for severe Crohn's disease. Twenty-six persons with lymphoma have been identified by MedWatch, FDA's post-market adverse event surveillance system. A manuscript is now in preparation describing the findings of the initial investigation. Available data do not permit drawing a firm conclusion regarding the etiologic relationship between exposure to these medications and the subsequent development of lymphoma. Additional analytic epidemiologic study will be required to resolve this important question.